Vol. 34, No. 26, December 1969
SYNTHESIS OF trUnS,trUnS-a-FARNESENE 3789
The Synthesis of trans,trans-a-Farnesene' GOTTFRIED BRIEGER,TERRY J. NESTRICK, AND CHARLES R~CKENNA Department of Chemistry, Oakland University, Rochester, Michigan Received May 9, 1969 The stereospecific preparation of tran,trans-a-farnesene by rhodium chloride catalyzed isomerization of trans-@farnesene is reported. In addition, conjugated isomers, probably allofarnesenes, are formed. The KHSOIcatalyzed dehydration of nerolidol has been investigated, yielding products identified as a- and P-farnesene, @-bisabolene, and 6-bisabolene. The base-catalyzed dehydration of farnesol has been reinvestigated. Only @-fameseneis formed, along with a mixture of CI,hydrocarbons identified as 2,6,1O-trimethylundeca-2,4,9triene and 2,6,10-trimethy1undeca-1,5,9-triene.
While 0-farnesene has been known for a considerable time, and is in fact a constituent of several essential oils,2 the corresponding a isomer has not been conclusively identified. Recently, a-farnesene has been discovered as a natural component of Granny Smith apple w a ~as~well ~ as, in~ the glandular secretion of an ant, Aphaenogaster lmgiceps (F. Sm.).3c It seemed of interest, therefore, to prepare a synthetic specimen of a-farnesene. We have accordingly examined the KHS04-catalyzed dehydration of nerolidol (I), a base-catalyzed dehydration of farnesol (11), and the isomerization of trans-pfarnesene (111), prepared by a method recently reported.4 Earlier workers have examined the dehydration of both farnesolj and nerolidoP with a variety of acidic catalysts. I n the early work, mixtures of acyclic and monocyclic sesquiterpenes were reported. However, structural assignments were based principally on analogous reactions (observed in the monoterpene series with linalool and geraniol. The considerable variations noted in the physical properties of these terpenes, such as p-farnesene, make it clear that these preparations were impure. A more recent study indicates that the mixture resulting from the KHS04-catalyzed dehydration of farnesol is in fact a complex mixture of
and y-curcurmene (VI) (reaction 1) were definitely identified, in addition to triterpene derivatives? Recently the base-catalyzed dehydration of farnesol has also been reported, leading principally to the production of trans-0-farnesene (111), in addition to minor amounts of a product with one less carbon atom formulated as IX.8 Acid-Catalyzed Dehydration of Nerolido1.-Treatment of nerolidol with KHS04 a t 170" results in a mixture of C15 hydrocarbons which, on gas chromatographic analysis, reveals four major components in the relative yields of 39.0 (111), 20.0 (VII), 19.0 (IV), and 22.0% (VIII) (reaction 2).
I1
VI1
VI11
Q?+*+@+ I
CHZOH
1
I
111
v
IV
VI
a t least twelve components, among which trans+ farnesene (111), P-bisabolene (IV), allofarnesenes (V), (1) Portions of this work were presented at the 156th National Meeting of the American Chemical Society, Atlantic City, N. J., Sept 1968. (2) W. Karrer, "Konstitution und Vorkommen der organiachen Pflanzenstoff e," Birkhausser, Verlag, Basel, 1958. (3) (a) F. E. Huelin and K. E. Murray, Nature, 210, 1260 (1966); (b) K. E. Murray, Aust. J . Chem., 22, 197 (1969); (0) G. W. K. Cavill. P. J. Williams, and F. B. Whitfield, Tetrahedron Lett., No. 23, 2201 (1967). (4) G . Brieger, J . Org. Chem., 82, 3720 (1967). (5) L. Ruzicka, Xelu. Chim. Acta, 6, 490 (1923); E. H. Farmer and D. A. Sutton, J . Chem. Soc., 116 (1942); F. Sorm, J. Mleziva, Z. Arnold, and J. Pliva, Collect. Czech. Chem. Commun., 14, (1949); F. Sorm, M. Zaroal, and V. Herout, ibid., 16, 626 (1951); V. Herout, V. Benesova, and J. Pliva, ibid., 18, 297 (1953); F. Sorm, M. Vrany, and V. Herout, ibid., 18, 364 (1953). (6) L.Ruzicka and E . Capato. Helu. Chim. Acta, 8 , 259 (1925).
Component 111, on the basis of infrared (ir), nuclear magnetic resonance (nmr), and mass spectrometric analysis, is trans-p-farnesene. The second component, VII, has a molecular weight of 204 according to mass spectrometric analysis. Its ultraviolet (uv) spectrum shows Amax 232 mp (e 23,400). This suggests the presence of a conjugated diene grouping. The ir spectrum shows absorptions a t 837 cm-', suggestive of the presence of trisubstituted double bonds. Bands at 893 and 990 cm-', as well as absorptions at 1609 and 1645 cm-', indicate the presence of a vinyl group. The nmr spectrum shows a multiplet at ca. T 8.39 (9 H), a singlet a t 8.27 (3 H), two peaks centered a t 8.00, a triplet a t 7.20 ( J = 7.0 Hz, 2 H), a series of peaks in the olefinic region with a center approximately a t 5.0 (5 H), and a quartet a t 3.69 (1 H). This latter absorption supports the presence of a vinyl grouping. The other assignments agree substantially with those recently reported for a sample of a-farnesene isolated from natural ~ o u r c e s . ~We therefore consider truns,trans-cu-farneseneas the most likely structure for component VII. The stereochemical assignment is discussed below. This evidence appears to establish for the first time definitively the production of a-farnes(7) Y.Naves, ibid.. CS, 1029 (1966). (8) A. Bhati, Perfum. Essent. Oil Record, 64, 376 (1963).
3790 BRIEGER,NESTRICK,AND MCKENNA ene from the dehydration of nerolidol. Naves was unable to isolate or identify a-farnesene in the dehydration of farnesol with KHS04, but inferred its possible presence from uv spectral data.' Component IV altio shows a molecular weight of 204 by mass spectrometry. The ir spectrum shows bands in accord with thost: available for p-bi~abolene.~The nmr spectrum of product IV is also essentially in agreement with that of p-bisabolene. Product VI11 has a molecular weight of 204 (mass spectrometry), Its ir spectrum shows weak absorptions a t 798, 826, and 1640 cm-l, suggestive of a trisubstituted double bond in a six-membered ring, and an acyclic trisubstituted double bond. The nmr spectrum confirms this assignment, since there are only two broad peaks in the olefinic proton region a t r 4.92 and 4.66 (approximately 2 H), essentially identical in chemical shifts with absorptions found for 0-bisabolene. These data, coupled with the observation that the mass spectrum closely resembles that of 0-bisabolene, suggests that the fourth product, VIII, is in fact another isomer of bisabolene, most likely the 6 isomer. It appears then that the course of KHS04-catalyzed dehydration is somewhat different from that for farnesol, in that detectable amounts of a-farnesene are formed in addition to the expected 0-farnesene and the isomeric bisabolenes. Base-Catalyzed Dehydration of Farneso1.-When farnesol is treated with KOH at 210°, a mixture of hydrocarbons is formed. Gas chromatographic analysis of the products indicates the presence of four components in the relative yields of 14.0 (IX), 4.2 (XI), 25.0 (X), and 62.0'30 (111) (reaction 3).
The Journal of Organic Chemistry
with this data would be 2,6,10-trimethylundeca-2,4,9triene (X). I n support of such a proposal, the ir spectrum closely resembles that of alloocimene, and bands a t r 4.65 and 4.33 are also found in the nmr of alloocimene. The major component is trans-p-farilesene (111). The base-catalyzed dehydration of farnesol is then characterized by considerable cleavage. A mechanism which accounts for the observed products proceeds by oxidation of the primary alcohol to a carboxylic acid, followed by decarboxylation of the isomeric @,-punsaturated acid.8v10 In the presence of strong base and high temperatures, double-bond isomerization is facile. No a-farnesene was detected. Isomerization of trans-p-Famesene.-Since the dehydration of nerolidol leads only to a small amount of a-farnesene, the transformation of the more readily available p-farnesene4 was also investigated. Several compounds derived from group VI11 metals have been reported as active in olefin isomerization. l 2 These include derivatives of Pt, Pd, Rh, and Ir. Recently, rhodium chloride trihydrate was used in a synthesis of a-sine~a1.l~ We applied this method to trans-p-farnesene. After treatment for 30 min a t 70°, trans-p-farnesene is quantitatively isomerized. The major component (57%) has bands in the ir a t 3091,1645,1609,989,893, and 839 cm-l. The nmr spectrum shows a quartet a t T 3.68,characteristic of the lone proton of a vinyl group, a triplet a t 4.60,attributed to the proton on the trisubstituted double bonds ( J = 7.0 Hz), several bands between 4.85 and 5.20 (5 H in all), a triplet a t 7.19 (J = 7.0 Hz, 2 H) attributable to the methylene flanked by two double bonds, absorption a t 8-00due to the remaining methylene protons, a peak a t 8.26 (3 H), I - 210" + 111, XI (3) and a multiplet a t 8.39 (9H). While comparison with the other possible stereoisomers is not a t present possible, the evidence available suggests strongly that the isomer formed is exclusively IX x the trans,trans form VII. In a careful study of the Component IX, according to mass spectrometric isomeric cis and trans forms of a- and p-ocimenes, analysis, has a molecular weight of 192,indicating the Ohloff l4 found that the lone vinyl proton of the cis form loss of one carbon ahom. Its ir spectrum shows peaks absorbed consistently a t the lower T value (AT = 0.38). a t 828 (trisubstituted double bond) and 887 and 1645 This is the largest shift reported, and ought therefore to cm-l (terminal methylene). The nmr spectrum shows be of diagnostic value. The absolute value of T 3.70 a singlet a t r 5.38 (2 H), suggestive of a methylene (tram-p-ocimene) and 3.69 (trans-a-ocimene) compares group, and a broad peak centered a t 4.94 (2H). These favorably with the value herein reported (3.68). The observations are in accord with a structure proposed by Bhati for the substance he calls "nor farnesene" (2,6,10- appearance of peaks for methyl protons in the ratio of 3:9 suggests that three of the methyl groups have trimethylundeca-l,5~,9-triene), although his structural similar stereochemical environments. The only other proposal was based principally on analogy to products isomer which could exhibit this spectrum would be the obtained from phytol with KOH.8 unlikely cis,& form. The minor component XI was not further investiThe ir spectra of the isomeric ocimenes suggest that gated. However, j ts gas chromatographic retention the stretching frequency of the conjugated double bond time suggests that it is also a C14 product. might also be used for stereochemical analysis. Both Component X has again a molecular weight of 192 trans forms have the higher wavenumber assigned (mass spectrometry). It shows a uv spectrum with (1608 for trans-8-ocimene and 1605 cm-l for tram-aAmax 238 mp (E 25,000), suggestive of a conjugated diene ocimene). Again the band found in the a-farnesene is system. I n accord with this are ir absorptions a t 960 consistent with this assignment (1609 cm-I). and 989 (trans-disubstituted conjugated double bond) Within the limitations mentioned above, we therefore and bands a t 1650 and 1610 cm.-' The nmr spectrum shows a poorly resolved triplet a t 7 4.92 (1 H), another (10) G. H. Hargreves and L. N. Owen, J . Chem. Soc.. 750 (1947). triplet a t 4.65 ( J = 7.5Ha, 1 H),adoublet at 4.33(1 H), (11) R. T. Arnold, 0. C. Elmer, and R. M . Dodson, J . Amer. Chem. Soc., 73, 4359 (1950). and a quartet a t 3.89 (1 H). A structure consistent (12) J. F. Harrod and A. J. Chalk, ibid.. 86, 1776 (1964). (9) The unpublished nnir spectrum was kindly provided by Dr. R. B. (13) E. Bertele and P. Schudel, Hels. Chim. Acta, 10, 2445 (1967). Bates. (14) G. Ohloff, J. Seibl. and E. sz. Kovats, Ann., 676, 83 (1964).
+ A
c,B-
A
A
+
Vol. 3.4, No. 1gj December 1969
SYNTHESIS OF tranS,tTanS-(w-FARNESENE 3791
assign the trans,trans stereochemistry to the a-farnesene produced by isomerization of trans-p-farnesene. A second product is produced by the isomerization process. It has a uv spectrum showing a maximum of 280 mp suggestive of more extensive conjugation. The ir spectrum shows bands which closely resemble those found in alloocimene with a trans orientation for the disubstituted double bond. A likely structure then is the Cu homolog of alloocimene, XIII. The stereochemistry has not been determined. Other more extensively conjugated isomers were also detected (reaction 4). RhClj'3H,0 ethanol
I11
*+ \ VI1
+
isomers (4)
XI11
The rhodium chloride catalyzed isomerization of trans-p-farnesene then provides the most suitable method presently available, short of total synthesis, for the production of a-farnesene. Experimental Section All ir spectra were taken as thin films, unless otherwise indicated using either a Beckman IR-5 or IR-12 spectrometer. Nmr spectra were taken as approximately 10% solutions in CCl, with tetramethylsilane reference. Values are reported as T values relative to tetramethylsilane. Dehydration of Nerolido1.-A mixture of nerolidol (5.0 g) and KHSO4 (5.0 g) in a distillation flask was placed into a preheated oil bath at 170'. Vacuum was applied and the crude products were separated by distillation. The product, bp 110-130" (15 mm), was dried over anhydrous KsCO3. The yield was 2.2 g or 43%. The product was analyzed on a 10 ft X I/, in. column packed with 20% DEGS-60-80 mesh Chromosorb W for 5 ft and 20% Apiezon L-60-80 mesh Chromosorb W for 5 ft, revealing four componentis, 111, VII, IV, VIII, which were collected for analysis. Relative abundance follows: 39.0 (111), 20.0 (VII), 19.0 (IV), and 22.07, (VIII). trans-P-Farnesene (III).-Spectral data follow: uv rnax (n-heptane) 224 mp ( 6 14,000); ir (0.25-mm cell) 3095 (m), 2970 (s), 2930 (s), 2730 (w), 1790-1820 (w), 1670 (w), 1645 (w), 1630 (w), 1692 (s), ea. 1440 (s), 1378 (sh), 1372 (s), 1150 (w), 1105 (m), 990 (s), 900 (sh), 890 ( s ) ,825-835 (m), 740-755 (w), ea. 670 cm-l (w); nmr r 8.42 and 8.35 (9 H), ea. 8.03 and M . 7.80 (8 H ) , 5.07 ( s ) , 4.95, and 4.70 (6 H), 3.70 (quartet, 1 H); mass spectrum, molecular ion a t m/e 204." This product was identical with trans-p-farnesene prepared as previously reported.' trans,trans-a-Famesene (VII).-Spectral data follow: uv max (95% ethanol) 232 mp (e 23,400); ir 3092 (w), 2975 (s), 2940 (s), 2880 ( s ) , 1645 (m), 1609 (m), 1450 (s), 1379 (m), 1110 (m), 1090 (w), 990 (s), 893 (s), cu. 837 cm-l (w); nmr T 8.39 (m, 9 H ) , 8.27 (s, 3 H), 8.00 (d), 7.20 (t, 2 H, J = 7.0 Hz), several bands between 5.33 and 4.48 (5 H), 3.69 (quartet, 1 H ) ; mass spectrum, molecular ion at m/e 204.15 p-Bisabolene (IV).-Spectral data follow: ir 3050 (w), 2950 (s), 2900 (s), 2840 ( s ) , 1640 (m), 1440 (s), 1370 (m), 1150 (w), 1105 (w), 1050 (w), 1020 (w), 990 (w), 955 (w), 912 (w), 887 (s), 826 (w), 796 cm-' (w); nmr T 8.39 and 8.33 (9 H), 7.95,5.34 (impurity?), 5.26 (s), 4.90 and 4.62 (2 H ) ; mass spectrum, molecular ion a t m/e 204.16 8-Bisabolene (VIII).-Spectral data follow: ir 3020 (sh), 2970 (s), &30 (s), 1640 (w), 1440 (s), 1370 (m), 1150 (w), 1105 (w), (15) The mas8 spectra were determined by Mr. R . Hites, at the Massachusetts Institute of Technology.
1050 (w), 990 (w), 955 (m), 915 (w), 890 (w),826 (w), 798 (w); nmr T 8.37 (12 H), 7.36 (t, J = 7.0 Hz, 2 H), 4.90 and 4.62 (2 H); mass spectrum, molecular ion a t 204 m/e 204.15 This spectrum resembles that of IV. Dehydration of Farneso1.-Farnesol (10.0 g ) and KOH (80.0 g) were combined in a beaker and placed in an oil bath heated to ca. 210°, with vigorous stirring. After 10 min, the brown mixture was poured into 1 1. of ice water and extracted three times with 200 ml of ether. The combined ether extracts were evaporated and the residue was distilled to give 3.6 g of olefins, bp 80-90' (0.06 mm). The product was analyzed on a 10 ft X I/, in. column containing 25% TCEP and 60-80 mesh Chromosorb W. Four components were detected in the following relative yields: 14.0 (IX), 4.2 (XI), 25.0 (X), and 62.07, (111). The products were separated by gas chromatography and analyzed. 2,6,1 0-Trimethylundeca- 1,5,9-triene (IX) .-Spec tral data follow: ir 3050 (m), 2960 (s), 2940 (s), 2860 (s), 1760 (w), 1645 (m), 1440 (s), 1370 (m), 1110 (m), 1050 (w),985 (w), 965 (w), 887 (s), 828 cm-' (w); nmr T 8.46 (s) and 8.35 (m, 12 H), ca. 8.0 (8 H), 5.38 (s, 2 H), 4.94 (2 H); mass spectrum, molecular ion a t m/e 192.15 AnaZ.I6 Calcd for C1&: C, 87.50; H, 12.50. Found: C, 87.75; H, 12.34. 2,6,10-Trimethylundeca-2,4,9-triene (X).-Spectral data follow: uv max (95% ethanol) 238 mp (e 25,000); ir 3000 (m), 2960 ( s ) , 2940 ( s ) , 2850 (s), 1650 (w), 1610 (w), 1440 ( s ) , 1370 (s), 1195 (w), 1095 (w), 1035 (w), 989 (m), 960 (s), 860 (m), 827 cm-' (w); mass spectrum, molecular ion a t m/e 192.16 AnaZ.16 Calcd for C14H24: C, 87.50; H, 12.50. Found: C, 87.34; H, 12.67. trans-&Famesene (III).-See properties given above. Isomerization of trans-p-Farnesene .-trans-p-farnesene (1.97 g) was combined with 120 mg of rhodium chloride trihydrate in 16 ml of absolute ethanol. The mixture was heated and stirred under nitrogen a t 70" for 30 min. The mixture was cooled, taken up in 30 ml of diethyl ether, and washed once with 75 ml of saturated NaHCO; solution and then several times with distilled water. The solvent was evaporated to give a quantitative recovery of material. Gas chromatography (25% TCEP and 30-60 mesh Chromosorb W 10 f t x in. column, 124") showed two major components, XI11 (24.5) and VI1 (57.3%). ah-Farnesene (XIII).-Spectral data follow: uv max (95% ethanol) 280 m l (E 12,000); ir 3078 (w), 3047 (w), 2970 (s), 2924 (s), 2729 (w), 1665 (w), 1645 (m), 1594 (w), 1440 ( s ) , 1378 (s), 1236 (w), 1110 (m), 987 (m), 958 (m), 900 (m), 827 (m), 797 cm-1 (w). trans,trans-a-Farnesene (VII).-Spectral data follow: uv max (95% ethanol) 233 mp (E 27,000); ir 3091 (w), 2970 (s), 2930 (s), 2885 (s), 1645 (m), 1609 (m), 1445 (s), 1383 (s), 1110 (m), 1092 (m), 989 (m), 893 (s), 839 cm-' (w) [reported ir spectra, 3085 (w), 1635 (m), 1600 (s), 985 (s), 890 (s), 835 (m),%>l7 and 3093 (w), 1667 (w), 1642 (m), 1609 (s), 990 (s), 893 (sISbl;nmr T 8.40 (m, 9 H), 8.26 (3 H ) , 8.00 (4 H), 7.19 (t, J = 7 Hz, 2 H), 5.20,5.11, 5.04,4.85, and4.60(t,3Hinall),3.68(quartet, 1 H ) [reported nmr spectrum,*b 8.39, 8.36 (m, 9 H), 8.26 (3 H), 8.00 (d, 4 H ) , 7.19 (t, 2 H), 4.9 (m, 5 H ) , 3.68( quartet, 1 H)]; mass spectrum,18m/e 204 (p, 7.3%), 189 (2.3), 161 (5.8), 135 (7.3), 119 (31.1), 107 (40.4),93 (82.2), 79 (36.4), 69 (51.8); 55 (50.2), 41 (100.0) (reported mass spectrum,3bm/e 204, 189, 161, 135, 119, 107, 93, 79, 69, 55, 41).
Registry No.-111, 502-60-3; IV, 21902-26-1 ; VII, 21499-64-9; VIII, 20266-07-3; IX, 13290-12-5; X, 21902-29-4; XIII, 2 1902-30-7. Acknowledgment.-Technical assistance was provided by Messrs. B. Crawford and D. Hachey. The mass spectrometric determinations by R. Hites are gratefully acknowledged. This work was partially supported by the Petroleum Research Fund of the American Chemical Society. (16) Analyses were performed by Spang Microanalytical Laboratories, Ann Arbor, Mich. (17) The small discrepancies between the reported6 values are apparently due to the use of a dilute carbon tetrachloride solution in one case.% The spectra are identical as thin films (private communication, Professor G. W. K. Cavill). (IS) The analysis was kindly provided by Dr. D. deJong, Wayne State University.
